Date of Award
Master of Science (MS)
Fu-Ming Zhou, M.D., Ph.D.
Kazuko Sakata, Ph.D. Jeffrey D. Steketee, Ph.D. Wen Lin Sun, M.D., Ph.D.
L-3,4 dihidroxyphenylalanine (l-DOPA) strongly stimulates motor activity in parkinsonian patients and animal models of Parkinson's disease. Severe striatal dopamine (DA) loss characterizes Parkinson's disease and its animal models. Given the canonical rate model of Parkinson's Disease pathophysiology based on differences in DA pharmacology manifesting as electrophysiological differences in striatal projection neuron (SPN) spike rates, SPNs should increase spiking during the motor response to l-DOPA. In fact, stimulating specific subsets of these neurons to spike in freely-moving wild type and parkinsonian animals causes or inhibits motor activity as predicted. However, pharmacological effects of DA deficiency, let alone those of DA replacement, on SPN spiking activity in freely-moving animals are poorly studied and ultimately unknown. Showing the activity of SPNs of both in-/direct pathways may help elucidate mechanisms by which l-DOPA increases motor activity to normal and sometimes abnormal levels; such mechanistic information would advance understanding about how DA is such a potent motor stimulant.
To this end, I devised a Top-hat u-array (with microdrive) for recording in the striatum while stimulating the reticulated substantia nigra. Using my micro-array, I tested l-DOPA's acute effect on SPN spiking activity within contexts that varied in DA deficiency according to the Pitx3Null mouse's Parkinson's-like gradient of striatal DA denervation. Evidently, chronic DA denervation renders SPNs hyper-responsive to l-DOPA and a D1 agonist, SKF 81297, as indicated by exaggerated SPN spike rate responses biased by low baselines in Pitx3Null mice compared to wild-type mice. However, this may be a motor network effect on spiking as it was found in both dorsal (DA-denervated) and non-dorsal (having residual DA) Pitx3Null striatal regions. Furthermore, antidromically identifying dorsal SPNs allowed us to putatively distinguish a particularly relevant subset (striatonigral, D1-SPNs or d[irect]SPNs) known to elicit movement; serendipitously we also identified putative fibers of passage that strongly resembled striatal interneurons. D1-SPNs in Pitx3Null animals had baselines about an order of magnitude significantly below those in wild-type, and all increased firing more so in Pitx3Null than wild-type mice after drug injections, which lends some credence to the hypothesis that direct pathway SPNs are hyper-responsive during l-DOPA-induced normal and abnormal motor behavior secondary to DA depletion. Furthermore, they uncover a need to incorporate more neural factors in explaining electrophysiological effects attributable to DA denervation and restoration pharmacology. The latter data (putative fibers) tempt the interpretation that cortical axons of passage are being mistaken for striatal fast-spiking interneurons in the literature more often than not.
Sagot, Ben (https://orcid.org/0000-0002-9141-4369), "Pitx3Null Mutant (Striatal Dopamine-Deficient) Mice Have Exaggerated Spiny Projection Neuron Responses to l-DOPA and D1 Agonism and Lack Baseline Striatonigral Spiking" (2017). Theses and Dissertations (ETD). Paper 447. http://dx.doi.org/10.21007/etd.cghs.2017.0442.